Calixarenes and their use for sequestration of metals

ABSTRACT

Disclosed are “acid-amide” calixarenes of formula (I) wherein: L is [—CH 2 —] or [—O—CH 2 —O—] and may be the same or different between each aryl group; R 5  is H, halogen, or C 1 -C 10  aliphatic hydrocarbyl group, C 6 -C 20  aryl group, C 6 -C 20  hydrocarbyaryl group, any of which may optionally be substituted by one or more halo or oxo groups or interrupted by one or more oxo groups, and R 5  may be the same or different on each aryl group: R 1  comprises an optionally protected carboxy group: two groups out of R 2 , R 3 , and R 4  are H; the one group out of R 2 , R 3 , and R 4  not being H comprises an amide group. The amide group may be linked to a second calixarene to form a dimer. Also disclosed are methods of use of such calixarenes for the purposes of metal sequestration, especially of lanthanides and actinides. Also disclosed are calixarene dimer derivatives of the calixarenes of the invention. Also disclosed are processes for preparing the calixarenes and dimers.

[0001] The present invention relates to novel calixarenes, methods oftheir preparation, and uses thereof, in particular for the sequestrationof metals.

[0002] European Patent Publication No. 0 432 989 describes a number ofcalixarene and oxacalixarene derivatives as having metal sequesteringproperties, and reviews some of the prior art in this field.

[0003] In a first aspect of the present invention there is disclosedcalixarenes of the formula (I). The term calixarenes as used hereinafteris intended to embrace also oxacalixarenes,

[0004] wherein:

[0005] L is [—CH₂—] or [—O—CH₂—O—] and may be the same or differentbetween each aryl group.

[0006] R⁵ is H, halogen, or C₁-C₁₀ aliphatic hydrocarbyl group, C₆-C₂₀aryl group, C₆-C₂₀ hydrocarbylaryl group, any of which may optionally besubstituted by one or more halo or oxo groups or interrupted by one ormore oxo groups, and R⁵ may be the same or different on each aryl group.

[0007] R¹ comprises a carboxy group [—COO⁻] which may or may not beprotonated or protected. Suitable protecting derivatives include saltsand ester derivatives of the carboxylic acid.

[0008] two groups out of R², R³, and R⁴ are H

[0009] the one group out of R², R³, and R⁴ not being H comprises anamide group.

[0010] The combination of ‘acid’ (or protected acid) and ‘amide’ in thecalixarenes of the present invention is not found in the calixarenes ofthe prior art; this combination leads to unexpected and desirable metalsequestering properties (particularly for lanthanide and actinidecations) as will be further discussed below.

[0011] Preferably:

[0012] R² and R⁴ are H and R³ comprises the amide group; L is [—CH₂—] —between each of the aryl groups;

[0013] R⁵ is tertiary alkyl, especially butyl.

[0014] Preferably the carboxy group R¹ conforms to the general formula(A):

(A) [—X—COOR¹⁰]

[0015] wherein X is a C₁, a C₂ or a C₃ carbon chain being a part of analiphatic hydrocarbyl group, aryl group or hydrocarbylaryl group, any ofwhich may optionally be substituted by one or more halo, oxo or nitrogroups.

[0016] R¹⁰ is H or a protecting group being a salt or an Esterderivative. Salts include metal salts e.g. alkali (such as Li) or alkaliearth metals, or ammonium or substituted ammonium derivatives. Thechoice of salt should be made such as to prevent the cation interferingwith the operation of the calixarene in practice. Ester groups may beformed with C₁-C₁₀ aliphatic alkyl alcohols. C₆-C₂₀ aryl alcohols,C₆-C₂₀ hydrocarbylaryl alcohols, any of which may optionally besubstituted by one or more halo, nitro, or oxo groups or interrupted byone or more oxo groups. Examples include benzyl, p-methoxybenzyl,benzoylmethyl, p-nitrobenzyl, methyl, ethyl, butyl, t-butyl etc.

[0017] More preferably R¹ is of the general formula (B):

(B) [—(C.R⁶.R⁷)_(n)—COOR¹⁰]

[0018] wherein n is 1, 2 or 3 and R⁶ and R⁷ are H or halogen and can bethe same or different on each carbon.

[0019] Alternatively a may be of the general formula (C):

[0020] wherein n is 0 or 1 and R⁶ and R⁷ are H or halogen and can be thesame or different on each carbon and wherein the phenyl ring of thebenzoic acid group may be optionally substituted by one or more halo,oxo or nitro groups.

[0021] In each case it is preferable that n is 1 and R⁶, R⁷ and R¹⁰ areall H.

[0022] In unprotected acid embodiments, preferably the aliphatichydrocarbyl group, aryl group or hydrocarbylaryl group of X in formula(A) are substituted by one or more groups which cause a reduction in thepKa of the carboxy group with respect to the unsubstituted molecule e.g.nitro.

[0023] For instance the phenyl ring of the benzoic acid of formula (C)is preferably substituted by one or more groups which cause a reductionin the pKa of the carboxy group with respect to the unsubstitutedmolecule e.g. nitro.

[0024] Preferably the amide group R², R³, or R⁴ of formula (I) is of thegeneral formula (D):

[0025] wherein n is 1, 2 or 3 and R⁶ and R⁷ are H, halogen, or C₁-C₁₀aliphatic hydrocarbyl group, and can be the same or different on eachcarbon, and wherein R⁸ and R⁹, which may be the same or different, are Hor C₁-C₁₀ aliphatic hydrocarbyl group (optionally halo substituted)including a cycloaliphatic ring formed by R⁸ and R⁹ together.

[0026] In certain embodiments of the invention, as described in moredetail below, R⁸ or R⁹ may form a bridge to between a calixarene of thepresent invention and a further calixarene in order to produce a dimer.

[0027] Most preferably, the calixarene is of the formula (II):

[0028](5,11,17,23-tetra-tert-butyl-25-[hydroxycarbomylmethoxy]-27-[(N-diethylamino)carbomylmethoxy]-26-28-dihydroxy-calix[4]arene.)

[0029] This compound (“acid-amide”) has been found to be useful for theextraction of both divalent and trivalent metal ions such as Pb, Sr, Hg,Bi and Y; in particular Lanthanides (e.g. La) and Actinides (e.g. U).

[0030] Also embraced by the present invention are calixarenes of thegeneral formulae (I) and (II) but wherein some or all of phenyl groupsof the calixarene ring are further peripherally substituted in such away as not to compromise the advantageous combination of the carboxy andamide groups which form the central core of the present invention.Possible substituents include halogen, nitro, C₁-C₁₀ aliphatichydrocarbyl group, C₆-C₂₀ aryl group, or C₆-C₁₀ hydrocarbylaryl group,any of which may optionally be substituted by one or more halo or oxogroups or interrupted by one or more oxo groups. Indeed certainsubstituents (e.g. nitro) may be desirable in as much as they reduce thepKa values of the two hydroxy groups of the calixarene ring, therebymodifying the metal-chelating properties of the compound.

[0031] In a second aspect of the present invention there is disclosed amethod of sequestering metals comprising contacting the metals with acalixarene as described above.

[0032] Preferably the calixarene is used to complex metals at a pH of2-6, (most preferably pH 3-6) since at higher pHs there is an increasedrisk of the target metal precipitating. For instance, precipitation ofLanthanides occurs at fairly low pH (7.5 for La, 6.4 for Lu).

[0033] If required, additional complexing agents (such as are well knownto the skilled person) may be used to prevent precipitation of targetmetals. This allows the use of the calixarene at higher pHs, which willadvantageously reduce protonation of the carboxy and hydroxy groups. Theuse of such additional complexing agents can thus raise the usefulworking pH range of the calixarene to the point at which themetal-calixarene complex itself precipitates e.g. around pH 11.

[0034] The use of higher pHs (e.g. pH 7 to 10, preferably pH 9) may beparticularly advantageous for increasing the concentration of negativecharge in calixarenes having protected acid groups or incalixarene-dimers, which may otherwise be reduced by the protectinggroup or steric effects respectively.

[0035] If desired the environmental pH may be adjusted usingconventional methods of the art. For instance if it is desired to raisethe pH, then LiOH may be added. If desired, the pH may be buffered byusing an appropriate buffer such as are well known to those skilled inthis art e.g. citrate.

[0036] In all cases the lower pH limit of useful operation will bedependent on the pea of each chelating group in the calixarene, sincethat will dictate whether each (unprotected) carboxy or hydroxy groupwill be protonated at any given pH. It may therefore be desirable foreach group to have a low pKa e.g. when treating acidic waste streams forwhich the pH cannot be readily adjusted. The pKa of the protonatedcarboxy and the amide group of the calixarene of formula (II) is lessthan 3.

[0037] Preferably the calixarene is dissolved in a hydrophobic organicsolvent (e.g. dichloromethane) and this is mixed with an aqueous phasecontaining metal ions (e.g. in equal volumes).

[0038] The phases are then stirred or otherwise agitated, typically foraround 1 hour, followed by a 2 hour separation time.

[0039] Preferably the calixarene is present in excess over the metaltarget e.g. 25-fold, or 250-fold. The excess required for usefulextraction will depend on the nature of the metal target e.g. size,charge etc.

[0040] Preferably the metal target is U, Hg, Am, Pb, Sr, Bi, or Y forinstance in methods of environmental clean up. Alternatively the metalcould be an actinide such as Am or another lanthanide.

[0041] The calixarenes described above are such that the metal complexesformed with the target ion may be overall neutral without the necessityfor additional counter-anions. A further advantage is that thecalixarenes can be highly selective, thereby preventing unwanted metalions complexing all available sites.

[0042] A still further advantage of the methods of the current inventionis that the extracted metal ions can be recovered followingsequestration into the hydrophobic phase simply by contacting that phasewith a relatively small (with respect to the original metal-containingsample) volume of acid (e.g. 1M) thereby causing the pH to drop and themetal to become decomplexed and enter the acid aqueous phase. Thecalixarene can then be reused simply by evaporation of the solvent.

[0043] Alternatively, the extracted metal ions can be recoveredfollowing extraction simply by evaporating the solvent to leave themetal-calixarene complex.

[0044] Thus in preferred forms, e.g. using the ‘acid-amide’ above, theextraction methods of the present invention are both selective andefficient and do not require additional ions to operate. The nature ofthe extraction can be readily optimised by adjustment of the pH.

[0045] In a third aspect of the invention there is disclosed a solidphase-bound calixarene of the type described above e.g. polymer bound.For instance the calixarene may be physisorbed and immobilised ontopolystyrene divinyl benzene beads. Immobilisation of the calixarene on asolid phase support may assist in the extraction methods of theinvention. The preparation of such bound calixarenes would present noundue burden to those skilled in the art, in the light of the presentdisclosure in conjunction with the methods, or methods analogous to themethods, described by Harris et al. in U.S. Pat. Nos. 4,642,362 or4,699,966, or Parker in U.S. Pat. No. 4,447,585 or Tetrahedron 36461-510 (1980), or in European Patent Publication No. 0 217 656.

[0046] In a fourth aspect of the invention there is disclosed a processfor preparing the calixarenes described above. Intermediates for use inthe process form a fifth aspect of the invention.

[0047] In a sixth aspect of the invention there is disclosed acalixarene dimer comprising two calixarenes of formula (I) wherein theamide group of each is of the general formula (D) above, and wherein theR⁸ or R⁹ group of one calixarene is conjugated to the R⁸ or R⁹ of theother calixarene, optionally through a spacer group R¹¹, as shownschematically in formula (III):

[0048] The optional spacer group R¹¹ may be C₁-C₆ aliphatic hydrocarbylgroup, C₆-C₁₀ aryl group, C₆-C₁₆ hydrocarbylaryl group, any of which mayoptionally be substituted by one or more halo or oxo groups orinterrupted by one or more oxo groups. In the absence of a spacer groupthe R⁸ or R⁹ group of one calixarene is conjugated directly to the R⁸ orR⁹ group of the other. In any case it is preferable that there is only1, 2, 3 or 4 bridging atoms (preferably carbon atoms) between theNitrogen atoms of the two amide groups. Most preferably there is 2 or 3bridging carbon atoms. As described in more detail below, this spacingbetween the calixarenes may help to pre-stress the dimer into aparticular stable, low-energy, chelating conformation, and therebyenhancing the specificity for target metals with respect to calixarenemonomers. groups or interrupted by one or more oxo groups. In theabsence of a spacer group the R⁸ or R⁹ group of one calixarene isconjugated directly to the R⁸ or R⁹ group of the other. In any case itis preferable that thee is only 1, 2, 3 or 4 bridging atoms (preferablycarbon atoms) between the Nitrogen atoms of the two amide groups. Mostpreferably there is 2 or 3 bridging carbon atoms. As described in moredetail below, this spacing between the calixarenes may help topre-stress the dimer into a particular stable, low-energy, chelatingconformation, and thereby enhancing the specificity for target metalswith respect to calixarene monomers.

[0049] In a further aspect of the invention there is disclosed acalixarene of formula (IV):

[0050] wherein:

[0051] L is [—CH₂—] or [—O—CH₂—O—] and is the same or different betweeneach aryl group;

[0052] R⁵ is halogen, or is a C₁-C₁₀ aliphatic hydrocarbyl group, C₆-C₂₀aryl group or a C₆-C₂₀ hydrocarbylaryl group, any of which is optionallysubstituted by one or more halo or oxo or is interrupted by one or moreoxo groups, and R⁵ is the same or different on each aryl group;

[0053] R¹ is a carboxy group which is or is not protonated or protected;two groups out of R², R³ and R⁴are H; and

[0054] the one group out of R², R³ and R⁴ which is not H is a thioamidegroup.

[0055] In a preferred embodiment R² and R⁴ are H, R⁵ is the same on eacharyl group and is a tertiary butyl, L is [—CH₂—]. R¹ is

[0056] and R³ is

[0057] Alternatively, R² and R⁴ are H, R⁵ is the same on each aryl groupand is a tertiary butyl, L is [—CH₂—], R¹ is

[0058] and R³ is

[0059] In another embodiment of the invention there is disclosed amethod for preparing the calixarenes of formula (IV) above.

[0060] Furthermore, there is described a method for the sequestration ofmetals comprising contacting the metals with a calixarene of formula(IV) as described above.

[0061] The compounds, methods and processes of the present inventionwill now be described, by way of illustration only, through reference tothe following Figures and Examples. Other embodiments falling within thescope of the invention will occur to those skilled in the art in thelight of these.

FIGURES

[0062]FIG. 1 shows the acid-amide of the present invention.

[0063]FIG. 2 shows the efficiency of extraction of Lqa(III) byacid-amide as a function of concentration ratio of the two.

[0064]FIG. 3 shows the efficiency of extraction of La(III) by acid-amideas a function of the present of various anions (citrate, acetate,picrate).

[0065]FIG. 4 shows the efficiency of extraction of La (III) byacid-amide as a function of concentration of buffer (citrate).

[0066]FIG. 5 shows the efficiency of competitive extraction of differentLanthanide(III) cations by acid-amide in the presence of buffer(citrate).

[0067]FIG. 6 shows the efficiency of extraction of various metals byacid-amide in the presence of buffer (citrate).

[0068]FIG. 7 shows the efficiency of extraction of various metals byacid-amide in the absence of buffer.

[0069]FIG. 8 shows the structure of an acid-amide/Ln(III) complex, asdetermined by X-ray crystallography.

[0070]FIG. 9 shows the structure of an acid-amide/Lu(III) complex, asdetermined by X-ray crystallography.

[0071]FIG. 10 shows a calixarene dimer (designated 13b) according to thepresent invention.

[0072]FIG. 11 shows a calixarene dimer (designated 11b) according to thepresent invention, having an aryl spacer group between the Nitrogenatoms of the two amide groups.

[0073]FIG. 12 shows a calixarene dimer (designated 10) according to thepresent invention wherein the carboxy groups of the calixarenes havebeen protected by esterification with benzyl alcohol. The Nitrogen atomsof the two amide groups are linked via a 2-C ethyl bridge. The tertiarygroup of the Nitrogens (designated R⁹) is methyl in each case.

[0074]FIG. 13 shows a calixarene dimer (designated 11) according to thepresent invention wherein the carboxy groups of the calixarenes havebeen protected by esterification with benzyl alcohol. The Nitrogen atomsof the two amide groups are linked via a 2-C ethyl bridge. The tertiarygroup of the Nitrogens (designated R⁹) is hydrogen in each case.

[0075]FIG. 14 shows a calixarene dimer (designated 11a) according to thepresent invention, wherein the carboxy groups of the calixarenes havebeen protected by as an ethyl ester. The Nitrogen atoms of the two amidegroups are linked via a 3-C aromatic bridge. The tertiary group of theNitrogens is hydrogen in each case.

[0076]FIG. 15 shows a synthetic scheme for the acid-amide (954)

[0077]FIG. 16 shows a synthetic scheme for the azacrown-acidcalix[4]arenes A957 and A959.

[0078]FIG. 17 shows a synthetic route for the ester-thioamide A960 andthe acid-thioamide A961.

[0079]FIG. 18 shows the variation in % extraction of Cadmium (Cd) ionswith the molar ratio of Calixarene:Cd for acid-amide A954,ester-thioamide A960 and acid-thioamide A961 at pH=9.4.

EXAMPLES EXAMPLE 1

[0080] The pH changes associated with the combination of various of theagents used in the later examples was first measured in order to betterinterpret the findings. The standard extraction of dichloromethane andaqueous phase in equal volumes with 1 hour stirring plus 2 hoursseparation was employed. The La(III) was used at a concentration of 0.4mM, and the other agents were used in a ratio of 1:3:24 forLa(III):citrate:acid-amide. The results, measured to +/−0.1 pH units,are shown in Table 1. TABLE 1 Solution pH before pH after typeextraction extraction (no agents) 5.6 5.5 acid-amide 5.6 5.6 La (III)5.6 4.9 acid-amide La (III) 5.6 4.0 Citrate 6.0 6.1 Citrate acid-amide6.0 6.1 Citrate La (III) 6.0 6.0 Citrate acid-amide 6.0 6.1 La (III)

EXAMPLE 2

[0081] The efficiency of extraction of La(ill) by acid-amide as afunction of the concentration ratio of the two was measured at aninitial pH of 5.8 (FIG. 2). The pH was not maintained at this levelduring the experiment. A result of 90% extraction was achieved using alarge (250×) excess of acid-amide. It is postulated that this largeexcess was required because of a drop in pH during the course of theexperiment (see Example 1) which led to reduced deprotonation of thethree ionizable groups. In a similar experiment using UC₂ ²+only a 25×excess was required, possibly because as a divalant cation it can stillbe efficiently bound when the three ionizable groups of the acid-amideare partially protonated.

EXAMPLE 3

[0082] The effect of various anions on the efficiency of extraction isshown in FIG. 3. Citrate was found to be the best, probably because ofits buffering ability. In order to demonstrate that citrate is notitself involved in the actual extraction or complexation of La(III),LiOH was titrated into the mixture to retain pH 6 instead of using acitrate buffer. The level of extraction obtained (90% La(III)) wassimilar to that achieved with citrate, indicating that citrate is notactually required to achieve efficient acid-amide extraction. Thepostulated non-coordination of the La(III) by citrate when acid-amide ispresent indicates a high formation constant (i.e. tight binding) for theLa(III)/acid-amide complex.

EXAMPLE 4

[0083] The optimum amount of citrate required for La(III) extraction wasassessed (FIG. 4). The results indicate that a 3×excess over La(III) issuitable.

EXAMPLE 5

[0084] The efficiency of competitive extraction of various members ofthe Lanthanide series is shown in FIG. 5. The efficiency appears to dropoff across the series, probably as a result of the change in the size ofthe metal cations. The results with Lanthanides indicate that it islikely certain actinides such as Am(III) will also be efficientlyextracted.

EXAMPLE 6

[0085] The efficiency of extraction of various metals by acid-amide inthe presence of citrate was measured, the results being shown in FIG. 6.The results indicate high selectivity within the broad range of elementsassessed. The extraction of La, U, Hg, Sr, Eu, Tm, Lu, Bi, and Pb isespecially efficient, particularly as compared with the alkali and thesmaller alkali-earth metals, and various other transition metals.

EXAMPLE 7

[0086]FIG. 7 shows the efficiency of extraction of various metals byacid-amide in the absence of buffer. As can be seen, efficiency isreduced as compared with FIG. 6 (with buffer).

EXAMPLE 8

[0087] Single crystals of some metal/acid-amide complexes (Sm, Eu, Lu)were grown and analysed using X-ray crystallography. Results indicatethat the intermediate Lanthanides (Sm, Eu) prefer to form a neutraldimer structure of 2 acid-amide molecules binding 2 metal ions (see FIG.8 which shows an acid-amide/Ln(III) complex, wherein La=Sm or Eu). Thecomplex is a dimer in the solid state. The acid-amide takes up the coneconformation. The Sm cations are 8 coordinate, being bound to thedeprotonated phenolic oxygen atoms, the ethereal oxygen atoms, the amideoxygen and one of the carboxyl oxygens. The remaining two coordinationsites are made up from a methanol oxygen and a carboxyl oxygen from thesecond calixarene hence forming a bridge between the two calixarenes.

[0088] Molecular modelling suggested that all the larger Lanthanideswould form isomorphic structures and that only the smaller Lanthanides(Gd-Lu) would form discrete monomeric complexes. Lu (smallestLanthanide) forms a structure with 1 acid-amide and 1 metal ion whichrequires a counter anion for charge neutrality. FIG. 9 shows anacid-amide/Lu(III) complex with NO₃ as the counter ion. The Lu cation isshown to be seven coordinate, bound to the two phenolate oxygens, thetwo ethereal oxygens, the amide oxygen, one carboxylate oxygen and awater molecule.

[0089] These structures may help to account for the specificitydemonstrated in Examples 5 and 6.

EXAMPLE 9

[0090] Metal/acid-amide complexes were further investigated byextracting the complexes from the hydrophobic phase and determining themetal:acid-amide ratio. For La, Lu and U at pH 6 the M:L ratio was 1:1.This confirms the solid-state ratios determined for the largerlanthanides and Lu by X-ray crystallography in Example 8 (which were 2:2and 1:1 respectively). No X-ray data was obtained for U.

EXAMPLE 10

[0091] Acid-amide dimers and esters thereof were prepared based on theacid-amide calixarenes of the present invention, as described in morederail in Example 15 below. Some of these are shown FIGS. 10 to 14.

[0092] Compound 13b (FIG. 10) was prepared in order to mimic thecalixarene/Lanthanide complex of FIG. 8. The dimer did not complex La⁺³at pH 6, a more alkaline pH (i.e. pH 9) being required to quantitativelyextract La. This is possibly because steric hindrance may reduce La'sability to compete with protons for oxygen coordination sites at lowpHs. Metal:Ligand ratios in the solvent extracted complex weredetermined to be 0.54 i.e. for every 2 La:dimer. This suggests that allsix ionizable —OH groups are dissociated forming a complex similar tothat in FIG. 8. La, in the presence of Lu and U, at pH 9 ispreferentially extracted.

[0093] By contrast, U is quantitatively extracted at pH 6 (unlike La).The Metal:Ligand ratio at pH 6 was approximately 1:1 suggesting adifferent complex is forming to that formed by La at higher pH.

[0094] Compound 11b (FIG. 11) was prepared in order to optimise thebridging group between the calixarenes for U extraction. Themeta-di-phenylamine linkage restricts the two calixarene halves suchthat the carboxyl groups are close to each other. This is the predictedconformation in the metal complex, unlike the conformation in freesolution, wherein it is predicted that steric effects will mean that thehalves are diametrically opposed around the bridging group. The compoundextracted U much more efficiently at pH 9 than pH 6 (80% rather than20%). This is in contrast to Compound 13b above. The more alkalineoperating conditions of 11b may be more applicable to some clean upapplications.

[0095] In Compound 10 (FIG. 12) the carboxy group of the calixarenes hasbeen protected with benzyl alcohol. No U extraction occurred at pH 6 (aswith Compound 13b). Compound 11 (FIG. 13) is similar to compound 10 butwas generated using a different diamine. Again no extraction of Uoccurred at pH 6. Significant extraction of U and Hg occurred at pH 9notwithstanding the presence of the protecting group. This implies thata deprotonated carboxy group is not necessary for complexing U or Hg,but that the phenolic groups (deprotonated at high pH) are crucial toextraction. Compound 11a is protected with as an ethyl ester, and hasthe di-phenylamine linkage of compound 13b. Again no U extractionoccurred at pH 6.

[0096] It is clear that the pH dependent specificity of the dimericcompounds above give them utility in the selective extraction ofdifferent metals.

EXAMPLE 11

[0097] The acid-amide was physisorbed and immobilised onto polystyrenedivinyl benzene beads in an inert diluent. Solutions containing U werepassed through a chromatography column containing the beads at variousdifferent pHs at a flow rate of approximately 2 mls/min. A controlexperiment was carried out with blank beads. The results are shown Table2. As can be seen, above pH 2 extraction of U occurred, reaching 100% atpH 3. The kinetics were fast enough to absorb the U from the relativelyfast moving mobile phase. TABLE 2 Extraction Efficiency Acid-amide pHresin Blank 1  2 10 2 37 34 3 100  20 4 100  21 6 93 21 9 34  0

EXAMPLE 12

[0098] Synthesis of acid-amide (designated A954 below).

[0099] Synthetic Scheme

[0100] A954 was synthesised using the route shown in FIG. 15. Thebis-ester(A955) was synthesised following the literature method ofCollins et al (1991) J. Chem Soc., Perkin Trans., 1, 3137. Reaction ofp-tert-Butylcalix[4]arene with 2 equivalents of ethyl bromoacetate inacetone with potassium carbonate (as base) gave the bis-ester in goodyield. This was mono-deprotected using 1 equivalent of potassiumhydroxide in ethanol. Although the product contained traces of bothbis-ester and bis-acid as impurity, it was used without furtherpurification and the impurities removed in subsequent steps. Overnightreflux with thionyl chloride in dichloromethane gave the acyl chloridewhich was reacted immediately with excess diethylamine(indichloromethane with triethylamine present) to give the calixareneamide-ester (A953) in 72% overall yield. Finally, deprotection of theester group using potassium hydroxide in ethanol gave the desiredacid-amide (A954).

[0101] Detailed Synthesis

[0102] NMR data was compiled after each step, but is shown only for thefinal product.

[0103] A955: p-tert-Butylcalix[4]arene (10 g, 0.015 mol) and anhydrouspotassium carbonate (4.68 g, 0.34 mol) were slurried in dry acetone(distilled from CaSO₄) for 2 hours. Ethylbromoacetate (5.15 g, 0.031mol) was added, and the mixture stirred under nitrogen for three days.It was then filtered, the solvent distilled off and the residue driedunder vacuum. It was then slurried with cold ethanol to form a whitepowder and collected by filtration. This solid was washed with a furtherquantity of cold ethanol and dried under vacuum. Yield 8.97 g (73 %)

[0104] 951: bis-ester A955 (8.0 g, 9.76 mmol) was slurried in ethanol(600 ml). Potassium hydroxide (85% AR, 0.55 g, 9.76 mmol) added and themixture heated to reflux for 1-2 hours. On cooling the ethanol wasreduced in volume (to 50-100 ml) and 1M HCl added to precipitate theproduct. This was collected by filtration and washed with water(50 ml).The product was dried under vacuum.

[0105] Yield 6.95 g (90%) (Found: C, 73.84; H, 7.42; required C, 75.72;H. 7.62%);

[0106] A953: acid-ester 951 (5.0 g, 6.31 mmol) was refluxed overnightwith thionyl chloride (3.5 ml) in dry dichloromethane (100 ml). Thesolvent was then removed by distillation and the oily yellow residuedried under vacuum. Additions of dichloromethane (4-5 ml) were necessaryto help azeotrope off the last traces of thionyl chloride. When dry, theproduct was a glassy off-white solid. The acyl chloride ester was thendissolved in dry dichloromethane (50 ml). To this solution was addeddropwise, a solution containing dry diethylamine (dried over KOH) (0.98ml, 9.45 mmol) and dry triethylamine (dried over CaH₂ ) (0.87 ml, 6.31mmol) in dry dichloromethane (50 ml) over 30 minutes. After stirringovernight at room temperature, the solution was transferred to adropping funnel and washed with 1M HCl (50 ml) and then water (50 ml).It was then dried over MgSO4, filtered and the solvent removed in vacua.The crude product was purified by column chromatography on silica(Kieselgehl) using dichloromethane/methanol(98:2) eluent.

[0107] Yield 3.86 g (72%) (Found: C, 74.83; H, 8.13; N 2.12. requiredC,74.87, H, 8.72, N 1.61%)

[0108] 954: amide-ester, A953, (2.20 g, 2.48 mmol) was dissolved inethanol(150 ml) and potassium hydroxide (0.28 g, 4.96 mmol) added. Theresulting solution was then refluxed for 2 hours. After cooling to roomtemperature, the volume of the solution was reduced to ca. 25 ml byrotary evaporation. Addition of 1M HCl gave a white precipitate whichwas collected by filtration and washed with water. It was then dissolvedin dichloromethane (30 ml). washed with 1M HCl (30 ml) water (30 ml) andthen dried over MgSO4. The solvent was removed in vacuo to give a foamywhite solid. It was converted to a powder by dissolving in a minimum ofdichloromethane and adding hexane (30-40 ml)-evaporation to dryness gavea white solid. Yield 2.06 g (97%) (Found: C, 75.24; H, 8.77; N 1.97.required C, 75.33, H,8.51, N 1.69%).

[0109] NMR data (300 MHz, CDCl3) 1.07 (9H, s, —Bu) 1.11 (9H, s, —Bu),1.25 (18H, s, —Bu), 1.25 (3H, t, —CH₃), 3.38 (2H, d, Ar—CH₂—Ar), 3.38(2H, q, —NCH₂—), 3.42 (2H, d, J=13.02, Ar—CH₂—Ar), 3.55 (2H, q, —NCH₂—),4.22 (2H, d, J=13.0 Hz, Ar—CH₂—Ar), 4.30 (2H, d, J=13.3 Hz, Ar—CH₂—Ar),4.64 (2H, s, —OCH₂CO—), 4.78 (2 a, s, —OCH₂CO—), 6.93 (2H, s, Ar), 6.99(2H, s, Ar), 7.03 (2H, d, Ar), 7.06 (2H, d, Ar), 8.90 (2H, br s, —OH);(75.42 MHz, CDCl3) 13.02, 14.36, 31.12, 31.68, 32.17, 32.35, 33.91,34.05, 34.16, 40.78, 41.20, 72.44, 73.29, 125.24, 125.55, 126.10,127.21, 128.29, 132.71, 132.94, 142.32, 147.49, 148.51, 149.76, 150.11,150.21, 166.71, 170.44; FAB m.s., m/z 864 (M+2 Na⁺—H., 18%), 842 (M+Na⁺,100), 820 (M+10).

[0110] It should be noted that the synthesis of other calixarenesfalling within the claims of the present application may be readilyachieved by the skilled person in the light of the disclosure of thepresent document, particularly in combination with the common generalknowledge of the skilled person, as evidenced for example by theteaching and references of EP 0 432 989.

[0111]954/Metal Complex Synthesis

[0112] To prepare Ln(NO₃)₃ .nDMSO, n=3,4 Ln₂O₅ was dissolved in aminimum of nitric acid (fast exothermic process for large Ln, slowprocess for small Ln). To the resulting solution was added a 5-6 foldexcess of dimethyl sulphoxide. Ethanol and then diethyl ether were thenadded to precipitate the product. Occasionally, when the product oiledout, it was necessary to decant the mother liquor, add moreethanol/diethyl ether and then scratch with a glass rod. The product wasthen collected by filtration, redissolved in DMSO and precipitated withethanol/ether. The final product was collected by filtration and driedunder vacuum. All DMSO solvates gave elemental analyses in accordancewith their proposed structures.

[0113] A simpler method involved the use of Ln(NO₃)₃ penta andhexahydrates instead of the oxide. In this case the salt was twicedissolved in DMSO and precipitated with ethanol and diethyl ether.

[0114] The calixarene acid-amide A954 (0.0189 g, 0.023 mmol) wasdissolved in 1 ml DMF. To this solution was added Ln(NO₃)₃ .nDMSO (n=3or 4, 0.025 mmol) also in 1 ml DMF. After the further addition of 30microliters of triethylamine (excess), the solution was immediatelyfiltered and left to stand. As mentioned earlier, the larger lanthanidesprecipitated quite quickly from solution whereas the smaller ones tookconsiderably longer. The precipitated complex was then collected byfiltration and washed with a minimum of cold ethanol (ca. 0.5 ml) anddried under vacuum. Attempts were made to recrystallise these complexesfrom dichloromethane/ethanol. This typically involved dissolving thecomplex in dichloromethane (1.5 ml) and then adding ethanol (1 ml).After filtering, the solution was left to slowly evaporate.

[0115] For the larger lanthanides (La-Eu), the complex precipitatedfairly quickly from solution, and was then recrystallised fromdichloromethane/ethanol. In case of the Eu and Sm complexes, crystalssuitable for X-ray crystallographic analysis were isolated.

[0116] Precipitated from DMF/NEt:Sm complex of A954; Found: C, 64.0; H,7.2; N 3.3. required C, 64.3, H, 7.5, N 3.7%.

[0117] Eu complex of A954; Found: C, 63.9; H, 7.1; N 3.4. required C,64.2, H, 7.5, N 3.7%.

[0118] Recrystallised from ethanol/dichloromethane:

[0119] Eu complex of A954; Found: C, 65.6;H, 7.5; N 2.8. required C,65.6, H, 7.9, N 2.6%,

[0120] The smaller lanthanide complexes (Lu) less readily precipitatedfrom DMF solution than the larger ones described above, insteadcrystallising out only after a period of weeks.

EXAMPLE 13

[0121] Synthesis of azacrown-acid calix[4]arenes

[0122] In attempt to form discrete monomeric complexes across theLanthanide series, the azacrown-acid calix[4]arenes A957 and A959 (FIG.16) were prepared with the idea that the extra O-donor sites presentwould more easily satisfy the normal 8-10 coordination sphere of thelarger Lanthanides.

[0123] The synthetic scheme used in the synthesis of the simpleracid-amide (A354) was also applied in the synthesis of theazacrownacidcalix[4]arenes, FIG. 15. For the final deprotection step, inorder to eliminate the possibility of isolating alkali-metal complexesof the product, potassium hydroxide was used as base in the deprotectionof the N-aza-15-crown-5 ligand and sodium hydroxide in the case of theN-aza-18-crown-6 ligand.

[0124] Isolation of Complexes

[0125] Preliminary work was also begun on the isolation of theLanthanide complexes of these ligands, the majority of this involvingtheN-aza-15-crown-5 analogue only. The same methods were applied as forthe simpler acid-amide (A954) and, in general, the same observationsmade. Again the larger La cations formed complexes which readilyprecipitated from DMF solution. Attempts at recrystallisation of thesecomplexes from dichloromethane/ethanol again yielded X-raycrystallographic quality crystals of the Sm complex. Disappointingly,however, the anticipated monomeric complex was not formed. Instead, asimilar dimeric structure was adopted with the aza-crown folding awayand not coordinating to Sm.

EXAMPLE 14

[0126] U.V. Spectra

[0127] The observed maxima for the 954 acid-amide are listed in Table 3together with the corresponding values for selected complexes. Theextinction values given are approximate only. Given that the samplesizes measured were only about 1 mg, weighing errors could easilyaccount for apparent differences in absorption between related species.

EXAMPLE 15

[0128] Synthesis of acid-amide dimer. The dimers of Example 10 wereprepared by methods analogous to those above. In the case of 11a,compound A952 (FIG. 15) was prepared as described above. Two moleculesof A952 were dimerised with m-phenylenediamine in dichloromethane andtriethylamine. The yield was 68%. Compound 11b was prepared from 11a byregenerating the carboxy group with potassium hydroxide in ethanol. Theyield was 90%. The other dimers were prepared using different diamines(e.g. 1,2-di-(methylamino)ethane for 11 and 13b). Other protectinggroups can be added either as alcohols to the deprotected acid group, orincorporated into the precursor e.g. by substituting theethylbromoacetate used to prepare A955 in Example 12 with a bromylatedbenzyl ester. The diamine synthetic route is flexible in that a widevariety of spacer groups may be introduced between the calixarenehalves, allowing factors such as chain length, coordination etc. to beassessed. TABLE 3 Wavelength Maxima Compound/complex (nm) cm⁻¹M⁻¹ 954228 36000 282  9500 954/La 228 50000 260 (sh) 15000 307  9400 954/Sm 22846000 260 (sh) 13000 307  9600 954/Eu 228 48000 260 (sh) 15000 306  9700

EXAMPLE 16

[0129] Synthesis of the Ester-Thioamide A960

[0130] A960 was synthesised using the route shown in FIG. 17. Theprecursor A953 was prepared by the route shown in FIG. 15 and Example12. Lawesson's reagent (0.49 g, 1.2 mmol) was added to a solution ofester-amide A953 (1.0 g, 1. 1 7 mmol) in toluene (20 cm3) and themixture was heated at 80° C. for 4 hr. After cooling to roomtemperature, the toluene was removed under reduced pressure to give ayellow oil. This oil was dissolved in acetonitrile (15 cm³) and filteredthrough an alumina pad. Dropwise addition of water to the filtrateafforded a yellow precipitate, which was removed by filtration andrecrystallised from dichloromethane-ethanol to afford A960 as yellowprismatic crystals (0.95 g, 94%). The structure of this compound wasconfirmed by NMR, mass spectrometry and X-ray crystallography.

EXAMPLE 17

[0131] Synthesis of the Acid-Thioamide A961

[0132] A961 was synthesised using the route shown in FIG. 17. Theester-thioamide A960 was synthesized by the route shown in FIG. 17 andExample 16. Potassium hydroxide (0.036 g, 0.65 mmol) was added to asolution of ester-thioamide A960) (0.5 g, 0.58 mmol) in ethanol (25 cm³)and the solution heated under reflux for I hr. The ethanol was reducedin volume to approximately 5 cm³ and 1M HCl added to precipitate A961 asa pale yellow powder which was recrystallised from dichloromethanehexane(0.41 g, 85%). The structure of this compound was confirmed by NMR andmass spectrometry.

EXAMPLE 18

[0133]FIG. 18 shows the ability of the calixarenes A954, A960 and A961to extract cadmium ions at pH 9.4. Equal volumes of aqueous cadmiumcyanide solution (pH 9.4, [Cd²⁺=0.238 mMolar) and a solution of acalixarene in dichloromethane were mixed for 15 minutes by stirring. Theaqueous and organic phases were then allowed to separate for about 30minutes. The aqueous layer (Aq1) was then removed and the organic layerwas washed with a nitric acid blank (pH 9.4). The aqueous and organiclayers were allowed to separate for about 30 minutes, and the aqueouslayer was then removed (Aq2). Aq1 contained the cadmium ions that hadnot been extracted by the calixarenes, whereas Aq2 contained the cadmiumions that had been extracted by the calixarenes (and subsequentlyliberated by acidification of the organic layer). Aq1 and Aq2 were madeup to known volumes. ICP AES (inductively coupled plasma atomic emissionspectroscopy) was then used to determine the concentration of cadmiumions in the solutions. These figures can readily be used to determinethe percentage extraction of cadmium for a given ratio of concentrationof calixarene:cadmium.

[0134]FIG. 18 indicates that both the acid-thioamide A961 and theester-thioamide A960 are capable of extracting cadmium ions fromsolution. The order of efficiency of extraction is acid-thioamide,A961>acid-amide, A954>ester-thioamide, A960. The order can be explainedby the fact that both A961 and A954 have a proton that can be readilylost from the acid substituent. The resulting anion will attract andretain cadmium ions more effectively than the (usually uncharged) estergroup. The acid-thioamide (A961) forms complexes with cadmium morereadily than the acid-amide (A954) because the S atom in A961 is a“softer” atom than the 0 atom in A954, and is thus more polarisable andthus is more likely to form a complex with a Cd²⁺ ion, which is itself a“soft” ion.

1. Calixarenes of the formula (I)

wherein: L is [—CH₂—] or [—O—CH₂—O—] and may be the same or differentbetween each aryl group. R⁵ is H, halogen, or C₁-C₁₀ aliphatichydrocarbyl group, C₆-C₂₀ aryl group, C₆-C₂₀ hydrocarbylaryl group, anyof which may optionally be substituted by one or more halo or oxo groupsor interrupted by one or more oxo groups, and R⁵ may be the same ofdifferent on each aryl group. R¹ comprises a carboxy group which may ormay not be protonated or protected. two groups out of R², R³, and R⁴ areH the one group out of R², R³, and R⁴ not being H comprises an amidegroup.
 2. Calixarenes as claimed in claim 1 wherein R² and R⁴ are H andR³ comprises amide group.
 3. Calixarenes as claimed in claim 1 or claim2 wherein L is [—CH₂—] between each of the aryl groups.
 4. Calixarenesas claimed in any one of claims 1 to 3 wherein R⁵ is tertiary butyl. 5.Calixarenes as claimed in any one of claims 1 to 4 wherein the carboxygroup R¹ conforms to the general formula (A): (A) [—X—COOR¹⁰] wherein Xis a C₁, a C₂ or a C₃ carbon chain being a part of an aliphatichydrocarbyl group, aryl group or hydrocarbylaryl group, any of which mayoptionally be substituted by one or more halo, oxo or nitro groups; andR¹⁰ is H or a protecting group being a salt or an Ester derivative. 6.Calixarenes as claimed in claim 5 wherein R¹⁰ is H and the aliphatichydrocarbyl group, aryl group or hydrocarbylaryl group of formula (A)are substituted by one or more groups which cause a reduction in the pKaof the carboxylic acid group with respect to the unsubstituted molecule.7. Calixarenes as claimed in claim 5 wherein R¹ is of the generalformula (B): (B) [(C.R⁶.R⁷)_(n)—COOR¹⁰] wherein n is 1, 2 or 3 and R⁶and R⁷ are H or halogen and can be the same or different on each carbon.8. Calixarenes as claimed in claim 5 wherein R¹ is of the generalformula (C):

wherein n is 0 or 1 and R⁶ and R⁷ are H or halogen and can be the sameor different on each carbon and wherein the phenyl ring of the benzoicacid group may be optionally substituted by one or more halo, oxo ornitro groups.
 9. Calixarenes as claimed in claim 8 wherein R¹⁰ is H andthe phenyl ring of the benzoic acid of formula (C) is substituted by oneor more groups which cause a reduction in the pKa of the carboxy groupwith respect to the unsubstituted molecule.
 10. Calixarenes as claimedin any one of claims 5 to 9 wherein n is 1 and R⁶ and R⁷ are both H. 11.Calixarenes as claimed in any one of the preceding claims wherein theamide group R², R³, or R⁴ of formula (I) is of the general formula (D):

wherein n is 1, 2 or 3 and R⁶ and R⁷ are H, halogen, or C₁-C₁₀ aliphatichydrocarbyl group, and can be the same or different on each carbon, andwherein R⁸ and R⁹, which may be the same or different, are H or C₁-C₁₀aliphatic hydrocarbyl group which may be substituted by one or more halogroups, or may be a cycloaliphatic ring formed by R⁸ and R⁹ together, ormay be conjugated to a second calixarene.
 12. A calixarene of theformula (II) as described herein.
 13. Calixarenes of the generalformulae (I) or (II) wherein some or all of phenyl groups of thecalixarene ring are further peripherally substituted.
 14. A method ofsequestering metals comprising contacting the metals with a calixareneas claimed in any one of the preceding claims.
 15. A method as claimedin claim 14 wherein the method is carried out at a pH of between 2 and11.
 16. A method as claimed in claim 14 or 15 wherein the pH at whichthe method is carried is buffered.
 17. A method as claimed in claim 16wherein the buffer used is citrate.
 18. A method as claimed in any oneof claims 14 to 17 comprising the following steps: (i) dissolving thecalixarene in an hydrophobic organic solvent; (ii) mixing the organicsolvent with an aqueous phase containing metal ions; (iii) agitating theorganic solvent and aqueous phase together; (iv) recovering the metalfrom the organic phase.
 19. A method as claimed in any one of claims 14to 18 wherein the metal is selected from the list: a Lanthanide, U, Hg,Am, Pb, Sr, Bi, Y.
 20. A calixarene as claimed in any one of claims 1 to13 further characterised in that the calixarene is solid phase bound.21. A process for preparing a calixarene as claimed in any one of claims1 to 13 substantially as herein described with reference to Example 12and FIG.
 15. 22. A calixarene dimer comprising a calixarene as claimedin claim 11 wherein one of the R⁸ and R⁹ groups is conjugated to asecond calixarene.
 23. A dimer as claimed in claim 22 comprising twocalixarenes as claimed in claim 11 wherein the R⁸ or R⁹ group of onecalixarene is conjugated to the R⁸ or R⁹ of the other calixarene,optionally through a spacer group R¹¹, the optional spacer group R¹¹being C, C₆ aliphatic hydrocarbyl group, C₆-C₁₀ aryl group, C₆-C₁₆hydrocarbylaryl group any of which may optionally be substituted by oneor more halo or oxo groups or interrupted by one or more oxo groups. 24.A dimer as claimed in claim 23 wherein there is a 1, 2, 3 or 4 atomchain between the Nitrogen atoms of the two amide groups.
 25. A processfor preparing a dimer as claimed in any one of claims 22 to 24comprising the use of a diamine to conjugate two calixarene molecules.26. A process for preparing a dimer as claimed in claim 25 substantiallyas herein described with reference to Example
 15. 27. Calixarenes of aformula (I)

wherein: L is [—CH₂—] or [—O—CH₂—O—] and is the same or differentbetween each aryl group; R⁵ is H, halogen, or is a C₁-C₁₀ aliphatichydrocarbyl group, C₆-C₂₀ aryl group, or a C₆-C₂₀ hydrocarbylaryl group,any of which is optionally substituted by one or more halo or oxo groupsor is interrupted by one or more oxo groups, and R⁵ is the same ordifferent on each aryl group; R¹ is a carboxy group which is or is notprotonated or protected; two groups out of R², R³ and R⁴ are H; and theone group out of R², R³ and R⁴ which is not H is an amide group. 28.Calixarenes as claimed in claim 27 wherein R² and R⁴ are H and R³ is anamide group.
 29. Calixarenes as claimed in claim 27 wherein L is [—CH₂—]between each of the aryl groups.
 30. Calixarenes as claimed in claim 27wherein R⁵ is a tertiary butyl.
 31. Calixarenes as claimed in claim 27wherein the carboxy group R¹ is of the general formula (A): (A)[—X—COOR¹⁰] wherein X is a C₁, a C₂ or a C₃ carbon chain which is a partof an aliphatic hydrocarbyl group, aryl group or hydrocarbylaryl group,any of which is optionally substituted by one or more halo, oxo or nitrogroups; and R¹⁰ is H or a salt or an ester protecting group. 32.Calixarenes as claimed in claim 31 wherein R¹⁰ is H and the aliphatichydrocarbyl group, aryl group or hydrocarbylaryl group of formula (A) issubstituted by one or more groups which cause a reduction in the pKa ofthe carboxylic acid group with respect to an unsubstituted molecule. 33.Calixarenes as claimed in claim 31 wherein R¹ is of the general formula(B): (B) [—(C.R⁶.R⁷)_(n)—COOR¹⁰] wherein n is 1, 2 or 3 and R⁶ and R⁷are H or halogen and are the same or different on each carbon. 34.Calixarenes as claimed in claim 31 wherein R¹ is of the formula (C):

wherein n is 0 or 1 and R⁶ and R⁷ are H or halogen and are the same ordifferent on each carbon and wherein the phenyl ring of the benzoic acidgroup is optionally substituted by one or more halo, oxo or nitrogroups.
 35. Calixarenes as claimed in claim 34 wherein R¹⁰ is H and thephenyl ring of the benzoic acid of formula (C) is substituted by one ormore groups which cause a reduction in the pKa of the carboxy group withrespect to an unsubstituted molecule.
 36. Calixarenes as claimed inclaim 31 wherein n is 1 and R⁶ and R⁷ are both H.
 37. Calixarenes asclaimed in claim 27 wherein the amide group R², R³, or R⁴ of formula (I)is of the formula (D):

wherein n is 1, 2 or 3 and R6 and R⁷ are H, halogen, or a C₁-C₁₀aliphatic hydrocarbyl group, and are the same or different on eachcarbon, and wherein R⁸ and R⁹, which is the same or different, are H ora C₁-C₁₀ aliphatic hydrocarbyl group which is substituted by one or morehalo groups, or is a cycloaliphatic ring formed by R⁸ and R⁹ together,or is conjugated to a second calixarene.
 38. A calixarene of formula(II)


39. Calixarenes of the formulae (I) or (II) as claimed in claim 27 or 38wherein at least one of the phenyl groups of the calixarene ring arefurther peripherally substituted.
 40. A method of sequestering metalscomprising contacting metals with a calixarene as claimed in claim 27.41. The method as claimed in claim 40 wherein the method is carried outat a pH of between 2 and
 11. 42. The method as claimed in claim 40wherein the pH at which the method is carried out is buffered.
 43. Themethod as claimed in claim 42 wherein the buffer is citrate.
 44. Amethod of sequestering metals comprising the steps of: (i) dissolving acalixarene of claim 27 in an hydrophobic organic solvent; (ii) mixingthe organic solvent with an aqueous phase containing metal ions; (iii)agitating the organic solvent and aqueous phase together; and (iv)recovering the metal from the organic phase.
 45. The method as claimedin claim 40 or 44 wherein the metal is selected from a Lanthanide, U,Hg, Am, Pb, Sr, Bi and Y.
 46. The calixarene as claimed in claim 27wherein the calixarene is solid phase bound.
 47. The process forpreparing a calixarene of claim 27 comprising the sequential steps of:(i) bis-esterifying a calix[4]arene; (ii) deprotecting a first estergroup to form a first acid group; (iii) chlorinating the first acidgroup to form an acyl chloride; (iv) substituting the chlorine group inthe acyl chloride with a diamine moiety; and (v) deprotecting a secondester group to form an acid moiety.
 48. A calixarene dimer comprising acalixarene as claimed in claim 37 wherein one of the R⁸ and R⁹ groups isconjugated to a second calixarene.
 49. The dimer as claimed in claim 48comprising two calixarenes wherein the R⁸ or R⁹ group of one calixareneis conjugated to the R⁸ or R⁹ group of the other calixarene, optionallythrough a spacer group R¹¹, the optional spacer group R¹¹ being a C₁-C₆aliphatic hydrocarbyl group, or a C₆-C₁₀ aryl group, C₆-C₁₆hydrocarbylaryl group any of which is optionally substituted by one ormore halo or oxo groups or is interrupted by one or more oxo groups. 50.The dimer as claimed in claim 49 wherein there is a 1, 2, 3 or 4 atomchain between the nitrogen atoms of the two amide groups.
 51. Theprocess for preparing a dimer as claimed in claim 48 comprising reacting2 equivalents of a calixarene bearing an acyl chloride substituent with1 equivalent of diamine.
 52. Calixarenes of a formula (IV)

wherein: L is [—CH₂—] or [—O—CH₂—O—] and is the same or differentbetween each aryl group; R⁵ is halogen, or is a C₁-C₁₀ aliphatichydrocarbyl group, C₆-C₂₀ aryl group, or a C₆-C₂₀ hydrocarbylaryl group,any of which is optionally substituted by one or more halo or oxo or isinterrupted by one or more oxo groups, and R⁵ is the same or differenton each aryl group; R¹ is a carboxy group which is or is not protonatedor protected; two groups out of R², R³ and R⁴ are H; and the one groupout of R², R³ and R⁴ which is not H is a thioamide group. 53.Calixarenes as claimed in claim 52 wherein: R² and R⁴ are H; R⁵ is thesame on each aryl group and is a tertiary butyl; L is [—CH₂—]; R¹ is

R³ is
 54. Calixarenes as claimed in claim 52 wherein: R² and R⁴ are H;R⁵ is the same on each aryl group and is a tertiary butyl; L is [—CH₂—];R¹ is

R³ is
 55. A method of sequestering metals comprising contacting metalswith a calixarene as claimed in claim
 52. 56. A method of sequesteringmetals comprising the steps of: (i) dissolving a calixarene of claim 52in an hydrophobic organic solvent; (ii) mixing the organic solvent withan aqueous phase containing metal ions; (iii) agitating the organicsolvent and aqueous phase together; and (iv) recovering the metal fromthe organic phase.
 57. A process for preparing a calixarene of claim 52comprising the sequential steps of: (i) bis-esterification of acalix[4]arene; (ii) deprotection of the first ester group to form afirst acid group; (iii) chlorination of the first acid group to form anacyl chloride; (iv) substitution of the chlorine group with a diaminemoiety to form an amide group; and (v) substitution of the oxygen groupin the amide moiety with a sulphur group to form a thioamide moiety. 58.The method according to claim 57 for preparing a calixarene of claim 52comprising a subsequent step of deprotecting the second ester group toform a second acid group.
 59. A process for preparing a calixarene ofclaim 27 comprising the sequential steps of: (i) bis-esterifying acalix[4]arene; (ii) deprotecting a first ester group to form a firstacid group; (iii) chlorinating the first acid group to form an acylchloride; and (iv) substituting the chlorine group in the acyl chloridewith a diamine moiety.